OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis.

Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.

A double-blind study of the efficacy of nimesulide in the treatment of ankle sprain in comparison with placebo.

In a randomised double-blind study, nimesulide 100mg twice daily for 8 days was compared with placebo in the treatment of 60 patients with ankle sprain. On day 4, three nimesulide-treated patients discontinued treatment because of resolution of their symptoms, whereas 11 patients in the placebo group discontinued as a result of worsening symptoms. A significantly greater reduction in pain, functional impairment and swelling was observed with nimesulide compared with placebo; moreover, the time to improvement was significantly shorter with the active treatment. The overall evaluation of efficacy favoured nimesulide over placebo (p < 0.001). Both medications were well tolerated, with 5 patients reporting mild gastralgia (4 treated with nimesulide and 1 with placebo), while 1 placebo-treated patient reported a mild gastrointestinal disturbance. These results suggest that nimesulide is an effective treatment for the short term management of post-traumatic pain states.

Nimesulide in the treatment of osteoarthritis. Double-blind studies in comparison with piroxicam, ketoprofen and placebo.

The efficacy and tolerability profiles of nimesulide (a nonsteroidal anti-inflammatory drug) were assessed in 3 comparative double-blind clinical trials that each recruited 60 patients with osteoarthritis of the hip or knee. The duration of each investigation varied with the comparator agent chosen: 2 weeks for placebo; 3 weeks for piroxicam; 2 months for ketoprofen. Nimesulide and ketoprofen were each administered orally as a 100mg dose twice daily, while piroxicam was administered orally as a single daily 20mg dose. In each study the principal efficacy parameters were the improvement in spontaneous pain, assessed using a visual analogue scale, and the degree of functional impairment evaluated using the severity index of Lequesne; the final judgement of efficacy was made by the physician. In all studies, nimesulide improved these and other efficacy parameters with an activity significantly superior to that of placebo and comparable with that of reference drugs.

Long term tolerability profile of nimesulide in the treatment of osteoarthritis.

As a primary objective, the safety profile of nimesulide was assessed in a nonblinded study that recruited 134 patients (aged 41 to 82 years) with osteoarthritis requiring long term treatment (> or = 1 year). Nimesulide (100mg orally twice daily) was well tolerated. No statistically significant differences were found between the number of patients of varying ages reporting adverse events. Moreover, most adverse experiences were found to be mild to moderate in intensity, with a prevalence of gastrointestinal disorders. The number of adverse episodes reported steadily decreased over the duration of the trial and no pathological changes in haematology and blood chemistry tests were found. Evaluation of efficacy revealed a progressive reduction in pain intensity with time.

Guidelines for clinical studies assessing the efficacy of drugs for the management of acute low back pain.

In this paper we propose guidelines for clinical trials aimed at assessing the efficacy of drugs for acute non-specific low back pain (LBP) with or without radicular pain, preliminary to their approval and registration. To this end, consensus statements were obtained from a group of experts in the fields of rheumatology, clinical medicine, public health and epidemiology. EBM resources were systematically used as references. Four diagnostic categories were defined: type 1--LBP with no radiation; type 2--LBP radiating no further than the knee; type 3--LBP radiating beyond the knee, but with no neurologic signs; and type 4--LBP radiating to a specific and entire leg dermatome, with or without neurologic signs. Studies should be designed on the basis of the claimed indications for the drug, but must be double-blinded whatever the indication. The duration of the study may be shorter for LBP type 1 or 2 (one week) than for LBP types 3 and 4 (up to one month), depending on the aim of the study and the indications for the drug. The comparator may be inactive (placebo) or active (for a superiority trial, e.g., versus paracetamol). Specific inclusion and exclusion criteria have been defined here for each category. An appropriate wash-out period for any drugs that could affect the pain status should be planned. Paracetamol may be allowed as rescue medication. The primary endpoint should be based on a validated pain assessment tool that may be either generic (type 1 or 2) or oriented (back and knee for types 3 and 4). Secondary endpoints could include the assessment of functional performance; the duration of any period of bed-rest; work limitation; a global assessment comprising pain at rest, standing and walking; the time elapsed before epidural injection, the prescription of other therapeutic agents, or surgery; and the use of rescue medication. Adverse events (AE) should be monitored systematically using a methodology that reflects the mode of action of the tested drug. With the application of these guidelines, LBP could serve as an appropriate disease for testing analgesic drugs. Rigorous evaluation may also help to improve the management of acute LBP.

Medico-economic analysis of diacerein with or without standard therapy in the treatment of osteoarthritis.

This 9-month pragmatic study compared 2 therapeutic regimens in the management of osteoarthritis of the hip and knee. Patients received either diacerein 100 mg/day plus standard osteoarthritic therapy for 6 months, followed by a 3-month monitoring period without diacerein, or standard therapy alone for the entire 9-month period. A total of 207 patients with osteoarthritis of the knee and hip were enrolled. Improvements in Lequense's functional index and quality-of-life scores (revised Arthritis Impact Measurement Scales Health Status Questionnaire and Nottingham Health Profile), and decreases in nonsteroidal anti-inflammatory drug and analgesic consumption were significantly greater with diacerein plus standard therapy than with standard therapy alone. The overall assessment of therapy by patients was good or excellent for 60% of those who received diacerein plus standard therapy, compared with 26% who received standard therapy alone. Medical and paramedical procedures carried out in addition to those stipulated in the protocol (medical consultations, physiotherapy, nursing, etc.), osteoarthritis-related, were fewer and less costly in the diacerein plus standard therapy group than in the standard therapy group. The average outpatient cost (in 1995 French francs) of osteoarthritis treatment in the standard therapy group was FF2272 compared with FF2360 in the diacerein plus standard therapy group. The cost-effectiveness ratios per point scored on Lequesne's index were FF1893 for the standard therapy group and FF1072 for the diacerein plus standard therapy group, leading to a saving of 43% with diacerein plus standard therapy. The marginal cost (additional cost corresponding to the clinical benefit obtained by adding diacerein to standard treatment) was FF88 per point scored on Lequesne's index.

Relief of acute low back pain with diclofenac-K 12.5 mg tablets: a flexible dose, ibuprofen 200 mg and placebo-controlled clinical trial.

OBJECTIVE: To assess efficacy and safety of diclofenac-K 12.5 mg tablets in the treatment of acute low back pain (low back pain). MATERIAL/METHOD: A multiple dose, double-blind, double-dummy, randomized, placebo-controlled, parallel group trial compared diclofenac-K (12.5 mg; n = 124) with ibuprofen (200 mg; n = 122) and placebo (n = 126) in patients with moderate-to-severe acute low back pain. The treatment consisted of an initial dose of 2 tablets followed by 1 or 2 tablets every 4-6 hours as needed (maximum 6 tablets/day) for 7 days. The primary efficacy outcome for the initial dose was TOTPAR-3, the summed total pain relief over the first 3 hours. Secondary initial dose outcomes included TOTPAR-6, summed pain intensity differences SPID-3 and SPID-6, time to rescue medication or remedicate, and the End of First Dose global efficacy assessment. The primary efficacy outcome for the flexible multiple dosing regimen was the End of Study global efficacy assessment. Secondary outcomes for multiple dosing included time to rescue medication over the entire study, the End of Day global efficacy assessments (daily over Days 1-7), pain intensity differences on the VAS measured at Visit 2 and 3, and change in Eifel algofunctional index. Safety/tolerability was assessed by recording adverse events. RESULTS: Diclofenac-K 12.5 mg demonstrated superiority vs placebo on the primary efficacy parameter and almost all secondary initial dose outcomes. With respect to the initial dose, diclofenac-K 12.5 mg was also significantly superior to ibuprofen 200 mg on SPID-3. Ibuprofen 200 mg was superior to placebo only on the End of First Dose global efficacy assessment. The flexible multiple dosing regimens of diclofenac-K and ibuprofen were both significantly superior to placebo on the End of Study global efficacy assessment, time to rescue medication over the entire study period, the End of Day global efficacy assessment on Days 1-2, pain intensity difference on the VAS at Visit 3 and the Eifel algofunctional index at Visit 3 (also at Visit 2 in diclofenac-K 12.5 mg group). Both active treatments were as well tolerated as placebo. CONCLUSIONS: The flexible multiple dosing regimen of diclofenac-K 12.5 mg (initial dose of 2 tablets followed by 1-2 tablets every 4-6 hours, max. 75 mg/day) is an effective and safe treatment of acute low back pain.

DHEP plasters as a topical treatment of knee osteoarthritis--a double-blind placebo-controlled study.

A double-blind, placebo (PBO)-controlled trial was carried out on 155 adult outpatients with painful (Huskisson's analogical scale > 40 mm) monolbilateral femorotibial and/or femoropatellar osteoarthritis of the knee, radiologically confirmed. Patients were randomly given either diclofenac hydroxyethylpyrrolidine plasters (DHEP, 78 patients), containing 180 mg of active drug each, or matched PBO (77 ptns). Plasters were applied b.i.d. (at 8 a.m. and 8 p.m.) on the affected joint, for 15 days. No NSAID treatment was allowed during the trial, while paracetamol was admitted from the 4th day on and its daily intake carefully recorded. Huskisson's test and Lequesne's index were assessed at days 0, 4, 7 and 15. Patients were asked to fill in a daily cared with Huskisson's scale and subjective evaluations. Differences in favour of DHEP were observed from the first assessment (4th d.) on Huskisson's scale and Lequesne's index (p < 0.001). According to the patients' subjective evaluation, pain decreased as soon as the first day in both groups, with significant differences in favour of DHEP (p < 0.005). Even the number of night awakenings recorded by the patient was significantly in favour of DHEP (p < 0.005). It is worth noting that these results were obtained in spite of a significant reduction of paracetamol intake in DHEP patients in comparison with PBO patients (p < 0.01). Tolerability was judged good or excellent in the majority of cases: only minor side effects occurred in five patients (4 PBO, 1 DHEP) and the interruption of treatment was required for only one of the PBOs. This study shows that DHEP plaster significantly differs from matched PBO in the improvement of pain and patient's condition in painful knee osteoarthritis.

Lowest effective single dose of diclofenac for antipyretic and analgesic effects in acute febrile sore throat.

OBJECTIVE: To compare the antipyretic and analgesic effects of a single oral dose of diclofenac potassium 6.25, 12.5 or 25mg with paracetamol 1000mg and placebo in patients with fever resulting from acute febrile sore throat. DESIGN AND SETTING: This was a multicentre, double-blind, double-dummy, randomised, placebo-controlled, parallel group study conducted at 21 primary-care centres throughout France. PATIENTS: In total, 343 adult patients with acute febrile sore throat (fever >/=38.0 degrees C) were randomised to the five treatment groups. INTERVENTIONS: Patients received one oral dose of medication. Fever, spontaneous throat pain and pain on swallowing were recorded over 6 hours. If acute symptoms persisted 2 hours after study drug administration, the patient was allowed to take rescue medication and discontinue the trial. RESULTS: The antipyretic effects of diclofenac potassium 6.25, 12.5 and 25mg and paracetamol 1000mg were significantly greater than placebo. The antipyretic effects of diclofenac potassium 12.5 and 25mg were numerically greater than paracetamol 1000mg, which was comparable to the effect of diclofenac potassium 6.25mg. The analgesic effects of the higher doses, diclofenac potassium 12.5 and 25mg, and of paracetamol 1000mg were significantly better than placebo. Summary efficacy measures over the first 4 hours post-dose showed a dose-response relationship among the diclofenac doses, with statistically significant differences on some outcomes between the 25mg and the 6.25mg doses. On the global efficacy evaluation for relief of fever and throat pain, patients rated both diclofenac potassium 12.5 and 25mg significantly higher than paracetamol 1000mg (p

[Treatment of rheumatoid arthritis. Comparative study of the effect of immunoglobulins G eluted from the placenta and of venoglobulins]. / Traitement de la polyarthrite rhumatoïde. Etude comparative de l'effet des immunoglobulines G éluées du placenta et de celui des Veinoglobulines.

A double-blind multicenter study comparing the effect of placenta eluted IgG and venoglobulins in the treatment of rheumatoid arthritis was conducted in 113 hospitalized patients. Rheumatoid arthritis was severe, classical (92 cases) or definite (21 cases), seropositive in 87 cases, with nodules in 32 cases; the mean duration of the disease was 10 years. The majority of patients had previously received numerous slow-acting drugs without result or with side-effects. A statistically significant decrease of all the quantitative indices but one (grip strength) was obtained with both products on the 8th day of treatment; the effect of placenta eluted IgG was statistically superior for the number of swollen joints (P less than 0.025), Ritchie's index (P less than 0.0005) and some extra-articular manifestations. There was no significant decrease in associated treatments and biological parameters (erythrocyte sedimentation rate, rheumatoid factor). Tolerance was excellent; some cases of benign venulitis were observed; treatment was never discontinued on account of side-effects. Further placebo-controlled of each of these immunoglobulins of placental origin are needed for firm conclusions to be drawn.

[Ibuprofen 800 mg in the treatment of arthrosis of the fingers or rhizarthrosis]. / L'ibuprofène 800 mg dans le traitement de l'arthrose des doigts ou de la rhizarthrose.

Sixty outpatients with osteoarthritis of the interphalangeal joints of the hands or trapezo metacarpal joints were included in a multicentre, randomised, double-blind, parallel-group study. Patients were assigned to ibuprofen 800 mg (n = 30) or a placebo (n = 30) in two daily doses after morning and evening meals, for 14 days. Patients were assessed at entry and after one and two weeks' treatment. On D7, overall efficacy assessments performed by the investigator and patient using a four-point scale and overall spontaneous pain evaluated by the patient showed changes in favor of ibuprofen 800 mg. On D14, all selected evaluation criteria showed improved results with ibuprofen compared to placebo (p < 0.01). Three patients in the ibuprofen 800 mg group and one in the placebo group experienced adverse events during the study. Neither the incidence nor the type of adverse events were significantly different in the two groups. The algofunctional index recently developed by R.L. Dreiser and evaluated during this study correlated significantly with spontaneous global pain and with physician and patient efficacy ratings on D7 and on D14, but should nevertheless be subjected to a further validation study.

Adherence to treatment of osteoporosis: a need for study.

UNLABELLED: Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis. INTRODUCTION: Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients. METHODS: An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting. RESULTS: The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence. CONCLUSION: Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis.

OBJECTIVE: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working group to assess the value of time to joint surgery as a potential therapeutic failure outcome criterion for osteoarthritis (OA) of the hip or knee in the assessment of potential structure modifying agents. METHODS: PubMed was searched for manuscripts from 1976 to 2004. Relevant studies were discussed at a 1-day meeting. RESULTS: There are no accepted guidelines for 'time to' and 'indications for' joint replacement surgery. A limited number of trials have examined joint replacement surgery within the study population. Several parameters, particularly joint space narrowing (interbone distance), correlate with surgical intervention. However, at the level of the knee, none of the parameters have positive predictive value for joint replacement surgery better than 30%. In contrast, lack of significant joint space narrowing has a strong negative predictive value for joint replacement surgery (>90%), that remains after controlling for OA pain severity. CONCLUSION: At this time, GREES cannot recommend time to joint surgery as a primary endpoint of failure for structure modifying trials of hip or knee OA-as the parameter has sensitivity but lacks specificity. In contrast, in existing trials, a lack of progression of joint space narrowing has predictive value of >90% for not having surgery. GREES suggests utilizing joint space narrowing (e.g., >0.3-0.7 mm) combined with a lack of clinically relevant improvement in symptoms (e.g., >/=20-25%) for 'failure' of a secondary outcome in structure modifying trials of the hip and knee.

A comparison of the efficacy of etodolac SR (Lodine SR) and etodolac (Lodine) in patients with rheumatoid arthritis or osteoarthritis.

The efficacy and safety of a sustained-release (SR) formulation of etodolac were compared with those of conventional etodolac in two separate, randomized, double-blind, multicenter, 6-week trials. This report presents an interim analysis of the data from these studies. One study included 174 patients with rheumatoid arthritis (RA): 58 received etodolac SR 400 mg once daily (q.d.), 59 received etodolac SR 600 mg q.d., and 57 received etodolac 200 mg twice daily (b.i.d.). The second study included 230 patients with osteoarthritis (OA): 80 patients received etodolac SR 400 mg q.d., 76 received etodolac SR 600 mg q.d., and 74 received etodolac 300 mg b.i.d. Efficacy was evaluated by physician's global and patient's global assessment (both studies), number of painful joints (RA study), number of swollen joints (RA study), pain intensity (OA study), and weight-bearing pain (OA study). The interim analyses of the data from the studies indicates that all three regimens produced significant improvements from baseline in all mean efficacy values at each assessment; there were no significant differences between the treatment groups. The incidence of study events, except for dyspepsia, was comparable among the treatment groups in each study; dyspepsia occurred at a significantly lower rate in patients treated with etodolac SR than in patients treated with the conventional formulation of etodolac. We conclude that etodolac SR is as effective and safe as conventional etodolac for the treatment of patients with RA or OA.

A double blind, placebo controlled study of niflumic acid gel in the treatment of acute tendinitis.

Percutaneously administered niflumic acid gel (Niflugel R, Laboratories UPSA, Rueil Malmaison, France) was compared to placebo in a double blind, placebo controlled, multicentre study in the treatment of acute upper and lower limb tendinitis. Fifty nine subjects were enrolled in three centres and were randomly allocated to receive treatment with 2.5% percutaneous niflumic acid gel or placebo gel applied three times daily for 7 days. Clinical evaluations were carried out on inclusion and after seven days of treatment. The variables measured were pain felt by the patient and the investigators' and patients' overall evaluation of the treatments' efficacy. The patients also kept a daily record of pain scores. Any adverse events that occurred were noted. The results showed that niflumic acid gel was significantly better than placebo in improving patient signs as regards overall efficacy ratings. Global evaluation of efficacy rated by the investigator showed that 25/29 patients (86.2%) were healed or improved in the niflumic acid gel group compared with 11/27 patients (40.7%) on placebo, p = < 0.01. The overall assessment of tolerance showed no difference between groups. Only two minor adverse effects were reported in patients treated with niflumic acid gel, and they did not require patients to stop treatment. The study findings indicate that treatment with topical niflumic acid gel is effective in the treatment of tendinitis and results in improved clinical signs at the end of 7 days.

Therapeutic trials in digital osteoarthritis. A critical review.

Although common, hand osteoarthritis is controversial and rarely used as a model for clinical trials in osteoarthritis. We found only 13 therapeutic trials conducted in digital or trapeziometacarpal osteoarthritis between 1983 and 1994. Eleven of these trials were published. Seven were on nonsteroidal antiinflammatory drugs given either per os (two trials, meclofenamate and ibuprofen) or percutaneously (one trial each on etofenamate, ibuprofen, and ketoprofen gel, and two trials on niflumic acid gel), three were on symptomatic slow-acting drugs (glycosaminoglycanes in two trials and chondroitin sulfate in one), and three were on miscellaneous agents (the muscle relaxant idrocilamide, as a gel; the antisubstance P agent capsaicin, also as a gel; and a spa treatment). We have reviewed the methodology and findings of these trials with the goal of determining the optimal approach to realize better standardized trials in the next future for identifying symptomatic slow-acting drugs and/or "chondroprotective" agents with beneficial effects in digital osteoarthritis.

Methodology of clinical trials in hand osteoarthritis. Issues and proposals.

Although very common, hand osteoarthritis has rarely been the focus of clinical trials aimed at determining whether old or new drugs are effective on its symptoms or anatomical course. In addition to the difficulties inherent to studies of osteoarthritis in general, the highly unpredictable course of hand osteoarthritis poses specific challenges. Hand osteoarthritis is only beginning to be considered a potentially useful model for therapeutic trials and clinical research, in addition to the two widely-used models, knee and hip osteoarthritis. Recent studies have provided new information on the clinical and roentgenographic course of hand osteoarthritis. An algofunctional index and a quantitative roentgenographic score have been developed and validated as tools for evaluating and monitoring hand osteoarthritis. These tools are now available for use during therapeutic trials. In this article, we will make a number of recommendations about the selection of patients and of quantitative evaluation methods. These recommendations take into account the specific features of hand osteoarthritis and of the various categories of drugs for osteoarthritis; they place special emphasis on the most recent drug classes, namely symptomatic slow-acting drugs for osteoarthritis and potentially "chondroprotective" agents.